As the world population continues to age, Alzheimer's disease (AD) is becoming a major health care concern. If novel successful therapies do not become available, the number of AD patients will rise from 5.4 million today to 15 million in 2050 in the US. This fact underscores the pressing need for better understanding the pathophysiology of AD and its risk factors, and discovering effective prevention strategies and therapies. Aging and a family history for the disease are the strongest risk factors for developing sporadic AD. In particular, having a mother with AD poses an individual at a much higher risk to develop the disease later in life than having a father with the disease. Longitudinal studies have shown that non-cognitive impaired individuals with a maternal history of AD display with aging a typical brain phenotype characterized by lower glucose metabolism, and higher A? plaques compared to controls. Despite extensive research, how aging and maternal factor(s) interact to modulate the susceptibility of developing AD remain unknown. We hypothesize that maternal dietary lifestyle during gestation is an important element that influences the susceptibility to develop AD in the offspring. In support of this hypothesis, our preliminary data show that gestational high sugar diet has an age-dependent effect on brain health in the offspring. In particular, compared with controls, offspring exposed to gestational high sugar diet manifest behavioral impairments, synaptic dysfunction, elevated A? levels and an up-regulation of Beta-secretase-1 (BACE-1). Our hierarchical hypothesis is: gestational dietary lifestyle modulates the susceptibility to develop an age-dependent AD phenotype in the offspring by promoting epigenetic modifications. To address this hypothesis, we will investigate the effect of gestational high sugar diet on cognitive function in the offspring; next we will study the effect of the same diet on their age-dependent development of AD pathophysiology; third we will determine the mechanism(s) underlying this effect. The significance of our proposal is twofold, since an increasing number of children are being exposed to high sugar food and beverages before birth and there is a pressing need to investigate the relationship between gestational environment and long-term mental health including factors that underlie individual susceptibility or resistance to cognitive decline and AD. Considering that evidence is mounting that AD processes begin decades before clinical symptoms are expressed, our research is also relevant since it will help identifying one of those early factors, such as dietary exposure in utero, that together with aging in the long term impact brain health and the susceptibility to develop AD later in life.